tbuckley/cabot-search huggingface dataset:
DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations
Authors: John Gallon, Antonio Rodriguez-Calero, Andrej Benjak, Dilara Akhoundova, Sina Maletti, Ursula Amstutz, Ekkehard Hewer, Vera Genitsch, Achim Fleischmann, Elisabeth J. Rushing, Rainer Grobholz, Ingeborg Fischer, Wolfram Jochum, Gieri Cathomas, Adeboye O. Osunkoya, Lukas Bubendorf, Holger Moch, George Thalmann, Felix Y. Feng, Silke Gillessen, Charlotte K.Y. Ng, Mark A. Rubin, Salvatore Piscuoglio
Journal: Cancer Research (2023)

Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
Mpox Outbreak Update—Reply
Authors: Carlos del Rio, Preeti Malani
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Acute hemolytic anemia after hematopoietic stem cell transplantation: An unusual invader
Authors: Mohammad Alhomoud, Rosemary Soave, Michael J. Kluk, Tsiporah Shore
Journal: American Journal of Hematology (2023)

69-year-old man with a history of diffuse large B-cell lymphoma (DLBCL) presented with severe acute hemolytic anemia 27 months after an autologous hematopoietic stem cell transplantation. Bone marrow aspirate revealed intracellular micro-organisms (arrows) located within the cytoplasm of red blood cells confirming the diagnosis of severe babesiosis.
Clinical Images: <scp>IgG4</scp>‐related disease: a giant cell arteritis mimic
Authors: Mahmut Kaymakci, Mohanad Elfishawi, Matthew J. Koster, Philip D. Hurst, Kenneth J. Warrington
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Association of War With Vaccination Dropout Among Children Younger Than 2 Years in the North Wollo Zone, Ethiopia
Authors: Muluemebet Kassa Mezen, Getasew Assefa Lemlem, Yemisrach Belete Biru, Abebaw Mengesha Yimer
Journal: JAMA Network Open (2023)

Importance A civil war that lasted for about 6 months in the North Wollo zone of Ethiopia destroyed numerous health care facilities. However, no studies have been conducted to determine the association of the war with vaccination dropout in the area. Objective To assess the association of war with vaccination dropout among children younger than 2 years in the North Wollo zone. Design, Setting, and Participants This population-based cross-sectional study was conducted in the North Wollo zone from April 1 to June 30, 2022. Participants included children younger than 2 years and their mothers. A multistage sampling technique was used to select the participants. Main Outcomes and Measures A vaccination dropout rate (yes or no) was assessed by interviewing mothers. Results The study included 449 children younger than 2 years and their mothers, 291 (64.8%) of whom were 20 to 34 years of age. Almost all of the mothers (426 [94.9%]) were married. More than half of the mothers (271 [60.4%]) had a primary level education. Seventy-one children (15.8%) in the area received all basic vaccinations. One hundred ninety-eight children (44.1%) who started vaccination prior to the war dropped out of the immunization program. Additionally, 64 children (14.3%) born during the war did not receive any vaccination. Losing a family member (adjusted odds ratio [AOR], 3.11 [95% CI, 1.63-5.93]; P = .001), not being informed about catch-up vaccination (AOR, 2.18 [95% CI, 1.39-3.43]; P &amp;amp;lt; .001), being a rural resident (AOR, 2.22 [95% CI, 1.37-3.58]; P &amp;amp;lt; .001), home birth (AOR, 1.75 [95% CI, 1.11-2.77]; P = .002), and length of war (AOR for 5 months, 0.51 [95% CI, 0.28-0.93; P = .04]) were associated with the outcome variable. Conclusions and Relevance The findings of this cross-sectional study suggest that nearly 60% of children in the North Wollo zone remained undervaccinated or unvaccinated. Stakeholders should make coordinated efforts to overcome the humanitarian crisis in the area and optimize the accessibility of health services.
Genome-Wide Association Study in Acute Tubulointerstitial Nephritis
Authors: Xu-Jie Zhou, Tao Su, Jingyuan Xie, Qiong-Hong Xie, Li-Zhong Wang, Yong Hu, Gang Chen, Yan Jia, Jun-Wen Huang, Gui Li, Yang Liu, Xiao-Juan Yu, Swapan K. Nath, Lam C. Tsoi, Matthew T. Patrick, Celine C. Berthier, Gang Liu, Su-Xia Wang, Huji Xu, Nan Chen, Chuan-Ming Hao, Hong Zhang, Li Yang
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA–DR β 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. Background Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. Methods We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. Results Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 −39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 −8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. Conclusions We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.
The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer
Authors: Juan Liu, Cen Zhang, Dandan Xu, Tianliang Zhang, Chun-Yuan Chang, Jianming Wang, Jie Liu, Lanjing Zhang, Bruce G. Haffty, Wei-Xing Zong, Wenwei Hu, Zhaohui Feng
Journal: Journal of Clinical Investigation (2023)

The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.
Modifiable Risk Factor Score and Fecundability in a Preconception Cohort in Singapore
Authors: See Ling Loy, Chee Wai Ku, Michelle Mei Ying Tiong, Carissa Shi Tong Ng, Yin Bun Cheung, Keith M. Godfrey, Shan Xuan Lim, Marjorelee T. Colega, Jun Shi Lai, Yap-Seng Chong, Lynette Pei-Chi Shek, Kok Hian Tan, Shiao-Yng Chan, Mary Foong-Fong Chong, Fabian Yap, Jerry Kok Yen Chan
Journal: JAMA Network Open (2023)

Importance Although multiple modifiable risk factors have been identified for reduced fecundability (defined as lower probability of conception within a menstrual cycle), no scoring system has been established to systematically evaluate fecundability among females who are attempting to conceive. Objective To examine the association of a risk score based on 6 modifiable factors with fecundability, and to estimate the percentage reduction in incidence of nonconception if all study participants achieved a minimal risk score level. Design, Setting, and Participants This population-based cohort study obtained data from the S-PRESTO (Singapore Preconception Study of Long-Term Maternal and Child Outcomes) prospective cohort study. Females of reproductive age who were trying to conceive were enrolled from February 2015 to October 2017 and followed for 1 year, ending in November 2018. Data were analyzed from March to May 2022. Exposures A reduced fecundability risk score was derived by giving participants 1 point for each of the following factors: unhealthy body mass index, unhealthy diet, smoking, alcohol intake, folic acid supplement nonuser, and older maternal age. Total scores ranged from 0 to 6 and were classified into 5 levels: level 1 (score of 0 or 1), level 2 (score of 2), level 3 (score of 3), level 4 (score of 4), and level 5 (score of 5 or 6). Main Outcomes and Measures Fecundability, measured by time to conception in cycles, was analyzed using discrete-time proportional hazards models with confounder adjustment. Results A total of 937 females (mean [SD] age, 30.8 [3.8] years) were included, among whom 401 (42.8%) spontaneously conceived within 1 year of attempting conception; the median (IQR) number of cycles before conception was 4 (2-7). Compared with participants with a level 1 risk score, those with level 2, 3, 4, and 5 risk scores had reductions in fecundability of 31% (adjusted fecundability ratio [FR], 0.69; 95% CI, 0.54-0.88), 41% (FR, 0.59; 95% CI, 0.45-0.78), 54% (FR, 0.46; 95% CI, 0.31-0.69) and 77% (FR, 0.23; 95% CI, 0.07-0.73), respectively. Assessment of the population attributable fraction showed that all participants achieving a minimal (level 1) risk level would be associated with a reduction of 34% (95% CI, 30%-39%) in nonconception within a year. Conclusions and Relevance Results of this study revealed the co-occurrence of multiple modifiable risk factors for lowered fecundability and a substantially higher conception rate among participants with no or minimal risk factors. The risk assessment scoring system proposed is a simple and potentially useful public health tool for mitigating risks and guiding those who are trying to conceive.
Cell‐Laden Scaffolds for Vascular‐Innervated Bone Regeneration
Authors: Chen Qin, Hongjian Zhang, Lei Chen, Meng Zhang, Jingge Ma, Hui Zhuang, Zhiguang Huan, Yin Xiao, Chengtie Wu
Journal: Advanced Healthcare Materials (2023)

Abstract For regeneration of highly vascularized and innervated tissues, like bone, simultaneous ingrowth of blood vessels and nerves is essential but largely neglected. To address this issue, a “pre‐angiogenic” cell‐laden scaffold with durable angiogenic functions is prepared according to the bioactivities of silicate bioceramics and the instructive effects of vascular cells on neurogenesis and bone repair. Compared with traditional cell‐free scaffolds, the prepared cell‐laden scaffolds printed with active cells and bioactive inks can support long‐term cell survival and growth for three weeks. The long‐lived scaffolds exhibited durable angiogenic capability both in vitro and in vivo. The pre‐angiogenic scaffolds can induce the neurogenetic differentiation of neural cells and the osteogenic differentiation of mesenchymal stem cells by the synergistic effects of released bioactive ions and the ability of vascular cells to attract neurons. The enhanced bone regeneration with both vascularization and innervation is attributed to these physiological functions of the pre‐angiogenic cell‐laden scaffolds, which is defined as “vascular‐innervated” bone regeneration. It is suggested that the concept of “vascular‐innervated scaffolds” may represent the future direction of biomaterials for complex tissue/organ regeneration.
Deciphering the Heterogeneity Landscape of Mesenchymal Stem/Stromal Cell‐Derived Extracellular Vesicles for Precise Selection in Translational Medicine
Authors: Ye Li, Yin‐Hsueh Chen, Bing‐Yun Liu, Qing Nie, Li‐Jun Li, Xu Duan, Lian‐Zhi Wu, Gang Chen
Journal: Advanced Healthcare Materials (2023)

Abstract Mesenchymal stem/stromal cell‐derived extracellular vesicles (MSC‐EVs) have been considered promising therapeutics for disease treatments. However, MSC‐EVs harvested from different tissues present unique biological features reflective of their origins. The heterogeneity of MSC‐EVs constitutes an important barrier to their precise application in clinical translation that may probably lead to uncertain therapeutic effects. To give hints for future clinical translation, five MSCs are employed, whose derived EVs are most intensively utilized, namely bone marrow mesenchymal stem/stromal cells (BMMSCs), umbilical cord stem/stromal cells (UCSCs), adipose‐derived stem/stromal cells (ASCs), dermal stem/stromal cells (DSCs) and dental pulp stem/stromal cells (DPSCs) and the heterogeneity landscape of the corresponding MSC‐EVs are documented. Overall, the basic parameters, stability, and biosafety of different MSC‐EVs are indiscriminate. Strikingly, UCSC‐EVs exhibit distinguishing productivity. UCSC‐EVs as well as DPSC‐EVs present better drug loading/delivery capacity. In addition, the heterogeneity of different MSC‐EVs in cargo diversity, cellular affinity, organ biodistribution, and therapeutic effects may cue the rational selection in different disease treatments. Through a combined assessment, a rational strategy is combined for selecting MSC‐EVs in future clinics. Offering a panoramic view of MSC‐EVs harvested from different tissues, the current study may provide guidelines for the precise selection of MSC‐EVs in next‐generation therapeutics.
Phase 1 first-in-human study of dalutrafusp alfa, an anti–CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors
Authors: Anthony W Tolcher, Michael Gordon, Kathleen M Mahoney, Anna Seto, Marianna Zavodovskaya, Chia-Hsiang Hsueh, Shuyan Zhai, Thomas Tarnowski, Juliane M Jürgensmeier, Susanna Stinson, Ahmed A Othman, Tianling Chen, James Strauss
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study ( NCT03954704 ) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling in patients with advanced solid tumors. Methods Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity. Results In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1–14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-β 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively. Conclusions Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-β pathways in oncology.
Adverse Pregnancy Outcomes—Risk Enhancers Whose Time Has Finally Arrived
Authors: Natalie A. Bello
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS‐CoV‐2 Antibodies, and Protein Profiling
Authors: Federico Ribet, Annika Bendes, Claudia Fredolini, Mikolaj Dobielewski, Michael Böttcher, Olof Beck, Jochen M. Schwenk, Göran Stemme, Niclas Roxhed
Journal: Advanced Healthcare Materials (2023)

Blood sampling is a common practice to monitor health, but it entails a series of drawbacks for patients including pain and discomfort. Thus, there is a demand for more convenient ways to obtain samples. Modern analytical techniques enable monitoring of multiple bioanalytes in smaller samples, opening possibilities for new matrices, and microsampling technologies to be adopted. Interstitial fluid (ISF) is an attractive alternative matrix that shows good correlation with plasma concentration dynamics for several analytes and can be sampled in a minimally invasive and painless manner from the skin at the point-of-care. However, there is currently a lack of sampling devices compatible with clinical translation. Here, to tackle state-of-the-art limitations, a cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes is presented. The fluid is volume-metered, dried, and stably stored into analytical-grade paper within the microfluidic device. The obtained sample can be mailed to a laboratory, quantitatively analyzed, and provide molecular insights comparable to blood testing. In a human study, the possibility to monitor various classes of molecular analytes is demonstrated in ISF microsamples, including caffeine, hundreds of proteins, and SARS-CoV-2 antibodies, some being detected in ISF for the first time.